Use of Tapentadol for Inhibiting and/or Treating Depression and Anxiety

ABSTRACT

The use of tapentadol (i) in the treatment of pain in a subject suffering from depression and/or from anxiety, and/or (ii) in the treatment or the inhibition of depression or anxiety.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/458,510, filed Apr. 27, 2012, which claims priority from U.S.provisional patent Application No. 61/480,621, filed Apr. 29, 2011, theentire disclosures of which are incorporated herein by reference.Priority is also claimed based on European patent application no. EP 11003 508.6, filed Apr. 29, 2011, the entire disclosure of which islikewise incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to the use of tapentadol in the (i)treatment of pain, preferably of neuropathic pain, more preferably ofneuropathic pain due to lumbar radiculopathy, in a subject sufferingfrom depression and/or from anxiety, and/or in the (ii) treatment or theinhibition of depression and/or of anxiety.

Tapentadol (CG5503), the chemical name for which is(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is asynthetic, centrally-acting analgesic that is effective for thetreatment of moderate to moderately-severe acute or chronic pain. Thecompound can be employed as the free base or its physiologicallyacceptable salts and solvates. Preparation of the free base is knowne.g. from U.S. Pat. No. 6,248,737 (=EP 693,475).

Tapentadol is a centrally acting analgesic with a dual mode of actionconsisting of μ-opioid receptor (MOR) agonism and norepinephrine (NE)reuptake inhibition. The efficacy, safety, and pharmacokinetic profileof tapentadol indicate that the drug is useful in treating acute as wellas chronic pain.

Subjects suffering from pain often fall into depression and anxiety,especially if the pain is chronic or neuropathic. In patients withchronic or neuropathic pain 8 to 50% have been reported to have currentmajor depression (Smith G R, The epidemiology and treatment ofdepression when it co-exists with somatoform disorders, somatization orpain. Gen Hosp Psychiatry 1992, 14: 265-276). In another analysis of1,016 patients, the prevalence of depression was 12% in individuals with3 or more pain complaints (Dworkin S F et al., Multiple pains andpsychiatric disturbance: an epidemiological investigation. Arch GenPsychiatry 1990, 47: 239-244).

The most serious consequences of major depression are suicide andincreased rates of suicidal ideation and suicide completion have beenreported by patients suffering from chronic pain conditions (Magni etal., Suicidality in chronic abdominal pain; an analysis of the HispanicHealth and Nutrition Examination Survey (HHANES). Pain 1998, 76:137-144). Oncology patients with concomitant pain and depression weresignificantly more likely to request assistance in committing suicide aswell as actively taking steps to commit suicide. In contrast those withpain in the absence of depression were unlikely to request theintervention of euthanasia and physician-assisted suicide (Emmanuel etal., Euthanasia and physician assisted suicide; attitudes andexperiences of oncology patients, oncologists and the public. Lancet1996, 347: 1810).

On the other hand, subjects suffering from depression and/or anxietyoften have pain symptoms, which can be attributed to a somatoformdisorder (psychogenic pain). The pain symptoms are physical symptoms,which typically do not have an identifiable physical origin. Instead,they are the result of internal psychological conflicts that areunconsciously expressed as physical signs.

It is evident that subjects suffering from depression and/or anxietyinduced by pain or inducing pain symptoms are in need of medicaments forthe treatment of both, the depression and/or anxiety as well as thepain.

US 2009/0215809 discloses pharmaceutical compositions comprising acrystalline prodrug of an antiepileptic drug, namely pregabalin((S)-3-(Aminomethyl)-5-methylhexanoic acid) for the treatment of certaindiseases and disorders, including, for example, neuropathic pain,generalized anxiety disorder, fibromyalgia, migraine, hot flashes,restless legs syndrome, and sleep disorders. The pharmaceuticalcomposition may additionally comprise an opioid agonist selected fromtramadol, tapentadol, and oxycodone as a second therapeutic agent.

Similarly, U.S. Pat. No. 7,868,043 discloses pharmaceutical compositionscomprising a mesophasic pregabalin prodrug and methods of use thereof.

US 2010/0297181 discloses methods for treating epilepsy, mentaldisorders and/or deficits in sensory organ by administering to patientstherapeutically effective amounts of AMPA receptor antagonists, i.e.antiepileptic drugs, in combination with one or more other activeingredients useful for treating epilepsy, mental disorders and/ordeficits in the sensory organ. Tapentadol is mentioned in a list ofsuitable active ingredients to be administered in combination with AMPAreceptor antagonists. As mental disorders, mood disorders, such asdepressions, are listed.

The use of antiepileptic drugs, however, can be detrimental because ithas been found that it can be associated with a significantly increasedrisk for suicide-related events in patients with depression (Arana etal., Suicide-related events in patients treated with antiepilepticdrugs. N Engl J Med 2010, 363: 542-551). Furthermore, a pharmaceuticalcomposition comprising a combination of an antiepileptic and tapentadolcan be disadvantageous because of adverse events caused by each drugitself and due to interactions of the drugs with each other,respectively.

Accordingly, there is a need for pharmaceutical compositions comprisinga single pharmacologically active ingredient for use in the treatment ofpain in a subject suffering from depression and/or anxiety, and/or foruse in the treatment or the inhibition of depression and/or anxiety,wherein the single pharmacologically active ingredient maysimultaneously or sequentially act as an antidepressant and as ananalgesic.

US 2009/0306050 discloses compounds, such as lofepramine, exhibiting anactivity as a potent norepinephrine (NE) reuptake inhibitor, and anactivity at the dopamine D2 receptor sites. It was found that thesespecial compounds are effective in the treatment and inhibition ofvarious diseases and disorders associated with norepinephrine reuptake,such as pain predominant-type depression and depression secondary tochronic or neuropathic pain. However, antidepressants such aslofepramine exhibit several nuisance side effects and several warningshave been reported.

M. Afilalo et al., Clin. Drug Investig. 2010, 30(8), 489-505 disclosesinformation concerning the efficacy and safety of tapentadol extendedrelease compared with oxycodone controlled release for the management ofmoderate to severe chronic pain related to osteoarthritis of the knee.

B. Kupferwasser et al., Osteoarthritis and Cartilage 2009, Vol. 17,Supplement 1, 179 discloses an evaluation of long-term treatment withtapentadol extended release and oxycodone controlled release in patientswith chronic low back or osteoarthritis pain.

R. Lange et al., Osteoarthritis and Cartilage 2010, Vol. 18, Supplement2, 147-148 discloses results from randomized, double-blind phase 3studies of tapentadol prolonged release in patients with moderate tosevere chronic nociceptive and neuropathic pain.

B. Kupferwasser et al., Osteoarthritis and Cartilage 2010, Vol. 18,Supplement 2, 149 discloses information concerning the health status ofpatients who received tapentadol prolonged release during an open-labelextension study.

S. Schwartz et al., Current Medical Research & Opinion, 27(1), 2011,151-162 discloses results of a randomized-withdrawal, placebo-controlledtrial concerning safety and efficacy of tapentadol ER in patients withpainful diabetic peripheral neuropathy.

Accordingly, there remains a need for improved pharmaceuticalcompositions comprising a single pharmacologically active ingredientuseful for treating pain and simultaneously or sequentially treatingdepression and/or anxiety.

SUMMARY OF THE INVENTION

It is an object of the invention to provide medicaments for thetreatment and inhibition of depression and/or of anxiety that haveadvantages compared to the medicaments of the prior art. This object hasbeen achieved by the invention as described and claimed hereinafter.

While the analgesic efficacy of tapentadol is generally known, it hassurprisingly been found that tapentadol is also effective in thetreatment or inhibition of depression and/or of anxiety, preferably ofdepression and/or of anxiety that is induced by pain in a subjectsuffering from pain, and of depression and/or of anxiety inducingpsychogenic pain.

In particular, in clinical trials concerning the efficacy of tapentadolagainst low back pain, depression (measured with HADS) was observed asundesired side effect. While in general, the occurrence of this symptomwas at the borderline with respect to its clinical relevance, in thepatient sub-population suffering from neuropathic pain, i.e. sufferingfrom low back pain with a neuropathic component, a significantoccurrence of depression was observed and tapentadol unexpectedlyprovided significant improvement.

In a first aspect, the invention is directed to the use of tapentadol in

-   (i) the treatment of pain, preferably of neuropathic pain, more    preferably of neuropathic pain due to lumbar radiculopathy, in a    subject suffering from depression and/or from anxiety, and/or-   (ii) the treatment or inhibition of depression and/or of anxiety,    with the proviso tapentadol is not administered in combination with    an antiepileptic.

Thus, the invention relates to, inter alia, the use of tapentadol in

-   a) the treatment of pain, preferably of neuropathic pain, more    preferably of neuropathic pain due to lumbar radiculopathy, in a    subject suffering from depression and/or from anxiety;-   b) the treatment of depression and/or of anxiety in a subject    suffering from depression and/or from anxiety;-   c) the treatment of depression and/or of anxiety in a subject    suffering from pain, preferably from neuropathic pain, more    preferably from neuropathic pain due to lumbar radiculopathy;-   d) the inhibition of depression and/or of anxiety;-   e) the treatment of pain, preferably of neuropathic pain, more    preferably of neuropathic pain due to lumbar radiculopathy, and the    simultaneous treatment of depression and/or of anxiety; and/or-   f) the treatment of pain, preferably of neuropathic pain, more    preferably of neuropathic pain due to lumbar radiculopathy, and    simultaneous inhibition of depression and/or of anxiety.

A second aspect of the invention relates to a method for

-   (i) the treatment of pain, preferably of neuropathic pain, more    preferably of neuropathic pain due to lumbar radiculopathy, in a    subject suffering from depression and/or from anxiety, and/or-   (ii) the treatment or the inhibition of depression and/or of    anxiety, comprising the administration of an effective amount of    tapentadol, with the proviso tapentadol is not administered in    combination with an antiepileptic.

For the purpose of the specification, “tapentadol” is intended toinclude (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,its physiologically acceptable salts and solvates thereof. Suitablephysiologically acceptable salts include salts of inorganic acids, suchas hydrochloric acid (tapentadol HCl), hydrobromic acid and sulfuricacid, and salts of organic acids, such as methane sulfonic acid, fumaricacid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid,tartaric acid, mandelic acid, lactic acid, citric acid, glutamic acid,acetylsalicylic acid, nicotinic acid, aminobenoic acid,

onic acid, hippuric acid and asparaginic acid. The preferred salt is thehydrochloride salt.

For the purpose of the specification, unless expressly stated otherwise,doses of tapentadol relate to the free base. Thus, when aphysiologically acceptable salt of tapentadol is used instead, its dosehas to be adapted to the equivalent dose of the free base. For example,a dose of “200 mg” means an amount of 200 mg of the free base or anyequivalent amount of a physiologically acceptable salt or solvatecorresponding to 200 mg of the free base (e.g. about 233 mg of thehydrochloride). If not expressly stated otherwise, doses are “peradministration”, not “per day”.

The term “depression” is known to persons skilled in the art. Depressionis a common mental disorder that presents with depressed mood, loss ofinterest or pleasure, feelings of guilt or low self-worth, disturbedsleep or appetite, low energy, and poor concentration. These problemscan become chronic or recurrent and lead to substantial impairments inan individual's ability to take care of his or her everydayresponsibilities. At its worst, depression can lead to suicide.Depression occurs in persons of all genders, ages, and backgrounds. Inthis regard it can further be referred e.g. to the InternationalClassification of Diseases (ICD-10), particularly to its Chapter V. Asused in the specification, the term “depression” preferably covershereditary depressions and depressions, which represent a reaction ofstressors in the environment, or both. Preferably, pain is regarded asstressor in the environment. Furthermore, the term “depression” alsocovers depressive disorders, such as mood disorder, major depressivedisorder, and dysthymic disorder. Preferably, the term “depression” alsorelates to depression induced by pain, i.e. depression that arises frompain in a subject suffering from pain. The depression is typicallycaused by the chronic nature of the pain.

As used herein, the “depression score” is a value determining the degreeof the depression. The scale of depression scores covers the range from0 to 21, wherein the degree of the depression is high in case of highvalues and low in case of low values. In a group of tested subjects,typically the mean or mediate values of depression scores aredetermined. The mean value is the sum of all depression scores dividedby the number of subjects. The mediate value is the middle depressionscore in the set of determined scores. Preferably, the “depressionscore” is defined as in the experimental section.

The term “anxiety” is known to the skilled person. Anxiety is one of thefeelings one experiences when under stress; physical, social, economic,psychological. Anxiety results in a feeling of impending doom, fear(which can be intense), dryness of mouth, sweating, restlessness, racingheart, butterflies in the stomach, itching and tingling all over thebody, shortness of breath, having to visit the bathroom repeatedly,inability to concentrate, make decisions, carry out work, eat or sleep.In this regard it can further be referred e.g. to the InternationalClassification of Diseases (ICD-10), particularly to its Chapter V. Asused herein, the term “anxiety” relates to an anxiety disorder.Preferably, the term “anxiety” also covers panic disorder, generalizedanxiety disorder, and somatoform disorders. Preferably, the term“anxiety” also relates to anxiety induced by pain, i.e. anxiety thatarises from pain in a subject suffering from pain. The anxiety istypically caused by the chronic nature of the pain.

As used herein, the “anxiety score” is a value determining the degree ofthe depression. The scale of anxiety scores covers the range from 0 to21, wherein the degree of the anxiety is high in case of high values andlow in case of low values. In a group of tested subjects, typically themean or mediate values of anxiety scores are determined and referred to.The mean value is the sum of all anxiety scores divided by the number ofsubjects. The medite value is the middle anxiety score in the set ofdetermined scores. Preferably, the “anxiety score” is defined as in theexperimental section.

As used herein the terms “inhibit” and “inhibition” refer only to aretarding or lessening of a condition.

As used herein the term “antiepileptic” relates to drugs used in thetreatment of epilepsy. The term “antiepileptic” preferably also covers“anticonvulsants”, which are used in the treatment of epilepticseizures. Thus, the terms “antiepileptic”, “anticonvulsant” and“anti-seizure drug” are to be understood as synonyms. According to theATC-index of the “WHO Collaborating Center for Drug StatisticsMethodology” antiepileptics (N03A) cover barbiturates and derivatives,hydantoin derivatives, oxazolidine derivatives, succinimide derivatives,benzodiazepine derivatives, carboxamide derivatives, fatty acidderivatives and other antiepileptics such as pregabalin (N03AX16).According to US 2010/0297181 AMPA receptor antagonists such as1,2-dihydropyridine compounds also exhibit an anti-seizure effect andare useful in the treatment of epilepsy. Thus, AMPA receptor antagonistsalso fall under the term “antiepileptic”. Dihydropyridine derivativesare also known as selective calcium channel blockers with mainlyvascular effects (C08CA) according to the ATC-index of the “WHOCollaborating Center for Drug Statistics Methodology”. Thus, calciumchannel blockers are also considered as being covered by the term“antiepileptic” in the specification.

As used herein, the term “psychogenic pain” preferably refers to painfulsymptoms, which are the result of internal psychological conflicts.These unconsciously expressed physical symptoms typically do not have anidentifiable origin. Instead, the painful symptoms are the result of asomatoform disorder, also known as pain disorder. The “somatization” ofpain belongs to painful symptoms of depressions and can be defined asthe disease “pain predominant-type depression”, wherein the depressionmanifests itself predominantly in the “somatization” of pain.Preferably, the pain disorder, i.e. the “somatization of pain”, alsoincludes hypersensitivity to pain. Furthermore, the pain disorder can beaccompanied by hypochondriasis.

As used herein, the “pain score” is a value determining the degree ofpain or a mixture of pains in a subject is suffering from pain. Thescale of pain scores covers the range from 0 to 21, wherein the degreeof pain is high in case of high values and low in case of low values. Ina group of tested subjects, typically the mean or mediate values of painscores are determined and referred to. The mean value is the sum of allpain scores divided by the number of subjects. The mediate value is themiddle pain score in the set of determined scores. Accordingly, the“neuropathic pain score” is a value determining the degree ofneuropathic pain, and the “nociceptive pain score” is a valuedetermining the degree of nociceptive pain. Preferably, the “pain score”is defined as in the experimental section.

According to the invention, tapentadol is used in the

-   (i) treatment of pain in a subject suffering from depression and/or    from anxiety, and/or-   (ii) treatment or the inhibition of depression and/or of anxiety,    with the proviso tapentadol is not administered in combination with    an antiepileptic.

Preferably, tapentadol is used in the

-   (i) treatment of neuropathic pain, more preferably of neuropathic    pain due to lumbar radiculopathy, in a subject suffering from    depression and/or from anxiety, and/or-   (ii) treatment or the inhibition of depression and/or of anxiety in    a subject suffering from neuropathic pain, more preferably from    neuropathic pain due to lumbar radiculopathy, preferably with the    proviso that tapentadol is not administered in combination with an    antiepileptic.

In one preferred embodiment, tapentadol is used in the treatment of painin a subject suffering from depression and/or from anxiety, wherein thepain is neuropathic pain, preferably polyneuropathic pain, morepreferably diabetic polyneuropathic pain.

In another preferred embodiment, tapentadol is used in the treatment ofpain in a subject suffering from depression and/or from anxiety, whereinthe pain is low back pain, preferably pain due to lumbar radiculopathy,having a neuropathic component, particularly a mononeuropathic componentor a polyneuropathic component. The neuropathic component can beassessed e.g. by painDETECT positive (for further details, it isreferred to the experimental section).

In a preferred embodiment, tapentadol is used in the treatment of painin a subject that can be considered opioid naïve. In a preferredembodiment, tapentadol is used in the treatment of pain in a subjectthat has been pre-treated with opioids, preferably weak opioids.

In a preferred embodiment, tapentadol is used in the treatment of painin a subject suffering from depression and/or from anxiety, wherein thepain is causative for depression and/or for anxiety, i.e. the paininduces depression and/or anxiety. Preferably, the pain and depressionand/or anxiety are simultaneously or sequentially treated. Morepreferably, the pain, which is causative for depression and/or foranxiety is a mixture of nociceptive and neuropathic pain, and issimultaneously or sequentially treated with depression and/or anxiety.Most preferably, the pain, which is causative for depression and/oranxiety is neuropathic pain, and is simultaneously or sequentiallytreated with depression and/or anxiety.

In another preferred embodiment, tapentadol is used in the treatment ofdepression and/or of anxiety in a subject suffering from depressionand/or from anxiety, which cannot be attributed to a pain. Preferably,the depression and/or anxiety can be attributed to a disability, to achronic disease, to chemotherapy, to a hospital stay, to side effects ofa medicament, and/or the like.

In another preferred embodiment, tapentadol is used in the treatment ofdepression and/or of anxiety in a subject suffering from pain, whereindepression and/or anxiety is causative for the pain, i.e. depressionand/or anxiety occurs with pain symptoms. The pain symptoms may beregarded as psychogenic pain. Preferably, the psychogenic pain anddepression and/or anxiety are simultaneously or sequentially treated.

In another preferred embodiment, tapentadol is used in the inhibition ofdepression and/or of anxiety. Preferably, depression and/or anxiety areexpected to develop due to a disability, to a chronic disease, tochemotherapy, to a hospital stay, to side effects of a medicament,and/or the like.

In another preferred embodiment, tapentadol is used in the treatment ofpain and the simultaneous treatment of depression and/or of anxiety.Preferably, the pain is chronic pain. More preferably, the pain isselected from the group consisting of neuropathic pain, nociceptivepain, psychogenic pain, phantom pain, and mixtures thereof. Still morepreferably, the pain is a mixture of nociceptive and neuropathic pain.Most preferably, the pain is neuropathic pain.

In another preferred embodiment, tapentadol is used in the treatment ofpain and the simultaneous inhibition of depression and/or of anxiety.Preferably, the pain is chronic pain. More preferably, the pain isselected from the group consisting of neuropathic pain, nociceptivepain, psychogenic pain, phantom pain, and mixtures thereof. Still morepreferably, the pain is a mixture of nociceptive and neuropathic pain.Most preferably, the pain is neuropathic pain.

According to the invention, tapentadol is not administered incombination with an antiepileptic. This is advantageous because the useof antiepileptic drugs for the treatment of a subject suffering fromdepression and/or anxiety is undesired. It has been found thatantiepileptic drugs can be associated with a significantly increasedrisk for suicide-related events in patients with depression. Preferably,tapentadol is not administered in combination with anticonvulsants andanti-seizure drugs. More preferably, tapentadol is not administered incombination with an antiepileptic selected from the group consisting ofbarbiturates and derivatives, hydantoin derivatives, oxazolidinederivatives, succinimide derivatives, benzodiazepine derivatives,carboxamide derivatives, fatty acid derivatives and other antiepilepticssuch as pregabalin. Most preferably, tapentadol is not administered incombination with pregabalin.

In another preferred embodiment, tapentadol is not administered incombination with AMPA receptor antagonists. AMPA receptor antagonistssuch as 1,2-dihydropyridines are classified as antiepileptics accordingto US 2010/0297181, which is incorporated by reference. Preferably,tapentadol is not administered in combination with any of theantiepileptic AMPA receptor antagonists mentioned in US 2010/0297181.More preferably, tapentadol is not administered in combination with1,2-dihydropyridines or derivatives thereof. Dihydropyridines are alsoknown as selective calcium channel blockers with mainly vascular effects(C08CA) according to the ATC-index of the “WHO Collaborating Center forDrug Statistics Methodology”. Consequently, tapentadol is preferablyalso not administered in combination with selective calcium channelblockers with mainly vascular effects. Most preferably, tapentadol isadministered neither with an antiepileptic nor a calcium channelblockers.

In one preferred embodiment, tapentadol is administered as the onlypharmacologically active ingredient in a medicament (medication).Preferably, tapentadol is administered via a route selected from thegroup consisting of orally, buccally, sublingually, transmucosally,intralumbally, intraperitoneally, transdermally, intraveneously,intramusculously, intragluteally, intracutaneously and subcutaneously.More preferably, tapentadol is administered orally.

In another preferred embodiment, tapentadol is administered once ortwice daily and/or at a daily dose within the range of from 25 to 600mg.

In another preferred embodiment, the dose of tapentadol to beadministered once daily or twice daily in the course of eachadministration amounts to 50 mg (±75%), more preferably 50 mg (±50%),still more preferably 50 mg (±30%), yet more preferably 50 mg (±20%),most preferably 50 mg (±10%), and in particular 50 mg (±5%).

In another preferred embodiment, the dose of tapentadol to beadministered once daily or twice daily in the course of eachadministration amounts to 100 mg (±75%), more preferably 100 mg (±50%),still more preferably 100 mg (±30%), yet more preferably 100 mg (±20%),most preferably 100 mg (±10%), and in particular 100 mg (±5%).

In still another preferred embodiment, the dose of tapentadol to beadministered once daily or twice daily in the course of eachadministration amounts to 150 mg (±75%), more preferably 150 mg (±50%),still more preferably 150 mg (±30%), yet more preferably 150 mg (±20%),most preferably 150 mg (±10%), and in particular 150 mg (±5%).

In yet another preferred embodiment, the dose of tapentadol to beadministered once daily or twice daily in the course of eachadministration amounts to 200 mg (±75%), more preferably 200 mg (±50%),still more preferably 200 mg (±30%), yet more preferably 200 mg (±20%),most preferably 200 mg (±10%), and in particular 200 mg (±5%).

In a preferred embodiment, the dose of tapentadol to be administeredonce daily or twice daily in the course of each administration amountsto 250 mg (±75%), more preferably 250 mg (±50%), still more preferably250 mg (±30%), yet more preferably 250 mg (±20%), most preferably 250 mg(±10%), and in particular 250 mg (±5%).

In another preferred embodiment, tapentadol is used in the treatment ofpain in a subject suffering from depression, wherein the pain isselected from the group consisting of pain being or being associatedwith panic disorder [episodic paroxysmal anxiety] [F41.0]; dissociative[conversion] disorders [F44]; persistent somatoform pain disorder[F45.4]; pain disorders exclusively related to psychological factors[F45.41]; nonorganic dyspareunia [F52.6]; other enduring personalitychanges [F62.8]; sadomasochism [F65.5]; elaboration of physical symptomsfor psychological reasons [F68.0]; migraine [G43]; other headachesyndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain[G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndromewithout pain [G54.7]; acute and chronic pain, not elsewhere classified[G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris,unspecified [120.9]; other specified disorders of nose and nasal sinuses[J34.8]; other diseases of pharynx [J39.2]; temporomandibular jointdisorders [K07.6]; other specified disorders of teeth and supportingstructures [K08.8]; other specified diseases of jaws [K10.8]; other andunspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; otherspecified diseases of anus and rectum [K62.8]; pain in joint [M25.5];shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhereclassified [M53.3]; spine pain [M54.]; radiculopathy [M54.1];cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain inthoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified[M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders,not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis,unspecified [M79.2]; pain in limb [M79.6]; other specified disorders ofbone [M89.8]; unspecified renal colic [N23]; other specified disordersof penis [N48.8]; other specified disorders of male genital organs[N50.8]; mastodynia [N64.4]; pain and other conditions associated withfemale genital organs and menstrual cycle [N94]; mittelschmerz [N94.0];other specified conditions associated with female genital organs andmenstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat[R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; otherchest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal andpelvic pain [R10]; acute abdomen [R10.0]; pain localized to upperabdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized toother parts of lower abdomen [R10.3]; other and unspecified abdominalpain [R10.4]; flatulence and related conditions [R14]; abdominalrigidity [R19.3]; other and unspecified disturbances of skin sensation[R20.8]; pain associated with micturition [R30]; other and unspecifiedsymptoms and signs involving the urinary system [R39.8]; headache [R51];pain, not elsewhere classified [R52]; acute pain [R52.0]; chronicintractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified[R52.9]; other complications of cardiac and vascular prosthetic devices,implants and grafts [T82.8]; other complications of genitourinaryprosthetic devices, implants and grafts [T83.8]; other complications ofinternal orthopaedic prosthetic devices, implants and grafts [T84.8];other complications of internal prosthetic devices, implants and grafts,not elsewhere classified [T85.8]; wherein the information in bracketsrefers to the classification according to ICD-10.

In a preferred embodiment, the invention relates to the inhibition ortreatment of pain selected from the aforementioned list of forms of painaccording to ICD-10, irrespective of whether the subject simultaneouslysuffers from depression and/or anxiety or not.

In a particularly preferred embodiment, the invention relates to theinhibition or treatment of pain, preferably neuropathic pain, morepreferably neuropathic pain due to lumbar radiculopathy, either in asubject simultaneously suffering from depression and/or anxiety; or in asubject simultaneously suffering neither from depression nor fromanxiety.

Lumbar radiculopathy is a nerve irritation caused by damage to the discsbetween the vertebrae. Damage to the disc occurs because of degenerationof the outer ring of the disc, traumatic injury, or both. As a result,the central softer portion of the disc can rupture (herniate) throughthe outer ring of the disc and abut the spinal cord or its nerves asthey exit the bony spinal column. This rupture is what causes thecommonly recognized pain of “sciatica” that shoots down the leg.

Preferably, the tapentadol is used to treat moderate or severe pain.More preferably, the tapentadol is used to treat severe pain.

In another preferred embodiment, the pain is paroxysmal or constant.Preferably, the tapentadol is used to treat pain which is constantlypresent.

In another preferred embodiment, the pain is central or peripheral.Preferably, the pain is central.

In another preferred embodiment, the pain is chronic pain. Preferably,the subject has experienced the pain for at least a week, preferably atleast a month, more preferably at least three months, still morepreferably at least six months, and most preferably at least a year.More preferably, the pain has increased during the time the subject hasexperienced the pain. Most preferably, the pain has had an intermittentcourse during this time.

In a preferred embodiment, the chronic pain is selected from the groupconsisting of cancer pain, chemotherapy-induced pain, upper back pain,back pain, inflammatory pain including pain associated with rheumaticdiseases, arthritic pain, ankylosing spondylitis pain, myofascial pain,pain associated with musculo-skeletal disorders, muscle pain, skeletalpain, joint pain, chronic pain associated with fibromyalgia, pain fromstrains/sprains, persistent post-operative pain, persistentposttraumatic pain, renal colic pain, irritable bowel syndrome-relatedpain, gastrointestinal pain, pelvic pain, abdominal pain, ischemic pain,angina pain, pain associated with claudication, pain accompanyingmyocardial infarction, vascular pain, pain associated with centralnervous system trauma, facial pain, migraine-related pain,headache-related pain, orofacial pain, persistent pain deriving fromdamaged or inflamed somatic tissue, and combinations thereof.Preferably, the chronic pain is back pain, more preferably low backpain. Preferably, the chronic low back pain is nociceptive pain,neuropathic pain, or a mixture thereof, more preferably, the chronic lowback pain is nociceptive mixed with neuropathic low back pain.

In another preferred embodiment, the pain is selected from neuropathicpain, nociceptive pain, psychogenic pain, phantom pain and mixturesthereof. Nociceptive pain may be causative for depression and/or foranxiety, i.e. induce depression and/or anxiety, whereas neuropathicpain, and phantom pain may be either causative for or resulting fromdepression and/or anxiety. Psychogenic pain typically results fromdepression and/or from anxiety, i.e. psychogenic pain may be regarded asa symptom of depression and/or anxiety.

Nociceptive pain is caused by stimulation of peripheral nerve fibersthat respond only to stimuli approaching or exceeding harmful intensity(nociceptors), and may be classified according to the mode of noxiousstimulation; the most common categories being “thermal” (heat or cold),“mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut,chili powder in the eyes). Nociceptive pain may also be divided into“visceral,” “deep somatic” and “superficial somatic” pain. Visceral painoriginates in the viscera (organs) and often is extremely difficult tolocate, and nociception from some visceral regions produces “referred”pain, where the sensation is located in an area distant from the site ofthe stimulus. Deep somatic pain is initiated by stimulation ofnociceptors in ligaments, tendons, bones, blood vessels, fasciae andmuscles, and is dull, aching, poorly-localized pain. Examples includesprains and broken bones. Superficial pain is initiated by activation ofnociceptors in the skin or superficial tissues, and is sharp,well-defined and clearly located. Examples of injuries that producesuperficial somatic pain include minor wounds and minor (first degree)burns.

Neuropathic pain is believed to be caused by a primary lesion ordysfunction in the nervous system. Neuropathic pains have beencategorized as peripheral neuropathic pain, due to lesion of theperipheral nervous system and central pain following lesions of thecentral nervous system. The prevalence of neuropathic pain is estimatedto be about 1%. Neuropathic pain has been shown to be rather therapyresistant. Accordingly, neuropathic pain has a high potential ofinducing depressions in a subject experiencing neuropathic pain.

In another preferred embodiment, the pain is neuropathic pain,nociceptive pain or a mixture thereof. More preferably, the pain isneuropathic pain.

In a preferred embodiment, the neuropathic pain is selected from thegroup consisting of diabetic neuralgia, monoradiculopathies, trigeminalneuralgia, post-herpetic neuralgia, persistent postoperative orposttraumatic pain, hyperalgia, allodynia, fibromyalgia, complexregional pain syndrome (CRPS), pain associated with multiple sclerosis,AIDS-related neuropathy, thalamic pain, paraplegic pain caused bymyelopathy, anesthesia dolorosa, low back pain, reflex sympatheticdystrophy/causalgia (nerve trauma), cancer pain, chemotherapy-inducedpain, post-thoracotomy pain, entrapment neuropathy (e.g., carpal tunnelsyndrome), and peripheral neuropathy (widespread nerve damage).

In one preferred embodiment, the neuropathic pain is polyneuropathicpain. Preferably, the pain is diabetic polyneuropathic pain.

In another preferred embodiment, the pain is a mixture of neuropathicand nociceptive pain, wherein the neuropathic pain score is higher thanthe nociceptive pain score. Preferred values for the neuropathic painscores and nociceptive pain scores are summarized as preferredembodiments E1 to E6 below.

E1 E2 E3 E4 E5 E6 Neuropathic ≧1 3 to 21 3 to 21 5 to 20 5 to 15 5 to 15pain score Nociceptive ≧0 1 to 20 1 to 10 1 to 10 1 to 5  0 pain score

In another preferred embodiment, the pain is mainly neuropathic pain,wherein neuropathic pain score is preferably in the range of from 1 to21, still more preferably from 3 to 21, yet more preferably from 5 to20, most preferably from 5 to 15.

In another preferred embodiment, the depression and/or anxiety isinduced by pain in a subject suffering from pain, wherein the pain ispreferably as defined above.

In another preferred embodiment, the depression and/or anxiety inducespsychogenic pain. Preferably, the psychogenic pain is back pain, chestpain, headache, muscle pain or a non-specific pain or ache, and can beregarded as a symptom for depression and/or anxiety.

In another preferred embodiment, the depression and/or anxiety inducesone or more symptoms selected from the group consisting of depressedaffect, anxiety, insomnia, suicidal thoughts, social inhibition, loss ofenergy, hopelessness, anhedonia, mood disturbances, irritability,disability, gastrointestinal disturbances, skin reactions, back pain,chest pain, headache, muscle pain and non-specific pains and aches.

The depression and/or anxiety a subject suffers from can be determinedby the depression and/or the anxiety scores respectively. The initialdepression and anxiety scores can be compared to the respective scoresafter the administration of certain amounts of tapentadol. Furthermore,the depression and anxiety scores can be assigned to certain pains. Themean and the mediate values for the depression and anxiety scores can bedetermined for a number of subjects. A reduction of these valuesindicates a decrease of depression and/or anxiety respectively.

In a preferred embodiment, the depression score is higher than theanxiety score. The values for the depression scores and anxiety scoresare summarized as preferred embodiments E7 to E12 below.

E7 E8 E9 E10 E11 E12 Depression score ≧1 3 to 21 3 to 15 5 to 10 5 to 125 to 10 Anxiety score ≧0 1 to 20 1 to 10 1 to 8  3 to 8  3 to 5 

In a preferred embodiment, tapentadol is used in the treatment of painin a subject suffering from depression and/or from anxiety, wherein thedepression and/or anxiety is simultaneously or sequentially treated,resulting in a reduction of the depression and anxiety scores and thepain scores. The values for the depression scores and anxiety scores aswell as the pain scores, i.e. neuropathic and nociceptive pain scores ina subject are summarized as preferred embodiments E13 to E20 below.

E13 E14 E15 E16 E17 E18 E19 E20 Depression score ≧1 3 to 21 3 to 15 5 to10 5 to 12 5 to 10 5 to 10 5 to 10 Anxiety score ≧0 1 to 20 1 to 10 1 to10 3 to 8  3 to 8  3 to 8  3 to 5  Neuropathic ≧1 3 to 21 3 to 21 5 to20 5 to 15 5 to 15 5 to 10 5 to 10 pain score Nociceptive ≧0 1 to 20 1to 15 1 to 10 1 to 5  0 0 0 pain score

Preferably, the reduction of anxiety is dependent on the pain theanxiety is associated with. The values for the anxiety scores before(initial) and after (final) the administration of tapentadol to asubject suffering from anxiety are summarized as preferred embodimentsE21 to E25 below.

E21 E22 E23 E24 E25 Anxiety score initial: initial: initial: initial:initial: associated with 2 to 20 2 to 20 2 to 9 4 to 7 5.9 (±1)nociceptive final: <90% final: <80% final: final: final: pain of initialof initial 1 to 8 3 to 6 4.5 (±1) value value Anxiety score initial:initial: initial: initial: initial: associated with 2 to 20 2 to 20 4 to11 6 to 9 7.9 (±1) neuropathic final: <80% final: <65% final: final:final: (presumed of initial of initial 1 to 8 3 to 6 4.8 (±1) paincompo- value value nent) Anxiety score initial: initial: initial:initial: initial: associated with 2 to 20 2 to 20 5 to 12 7 to 10 8.3(±1) neuropathic final: <80% final: <70% final: final: final: (defined)of initial of initial 1 to 8 3 to 6 4.5 (±1) value value

Preferably, the time period between the determination of the initial andthe final anxiety score is 6 months, more preferably 3 months, stillmore preferably 30 days, yet more preferably 20 days, most preferably 10days. Furthermore, the daily dosage of tapentadol is preferably withinthe range of from 25 to 600 mg, preferably from 50 to 300 mg, morepreferably from 50 to 150 mg.

Preferably, the reduction of depression is dependent on the pain thedepression is associated with. The values for the depression scoresbefore (initial) and after (final) the administration of tapentadol to asubject suffering from depression are summarized as preferredembodiments E21 to E25 below.

E26 E27 E28 E29 E30 Depression score initial: initial: initial: initial:initial: associated with 2 to 20 2 to 20 3 to 10 5 to 8 6.1 (±1)nociceptive final: final: final: final: final: <95% of initial value<85% of initial value 1 to 8 3 to 6 4.9 (±1) Depression score initial:initial: initial: initial: initial: associated with 2 to 20 2 to 20 5 to12 7 to 10 8.8 (±1) neuropathic final: final: final: final: final:(presumed <90% of initial value <75% of initial value 3 to 10 5 to 8 6.2(±1) pain component) Depression score initial: initial: initial:initial: initial: associated with 2 to 20 2 to 20 5 to 12 7 to 10 8.3(±1) neuropathic final: final: final: final: final: (defined) <90% ofinitial value <75% of initial value 2 to 9 4 to 7 5.8 (±1)

Preferably, the time period between the determination of the initial andthe final depression score is 6 months, more preferably 3 months, stillmore preferably 30 days, yet more preferably 20 days, most preferably 10days. Furthermore, the daily dosage of tapentadol is preferably withinthe range of from 25 to 600 mg, more preferably from 50 to 300 mg, mostpreferably from 50 to 150 mg.

In another preferred embodiment, tapentadol is used in the treatment ofdepression and/or anxiety, wherein the depression and anxiety scores arereduced. The reduction of the mean values for the anxiety scores due tothe administration of tapentadol over the time periods of 10, 20 and 30days are summarized as preferred embodiments E31 to E35 below. Each%-value indicates the remaining mean anxiety score after the definedtime period relative to the initial mean anxiety score.

Time E31 E32 E33 E34 E35 10 days <99% <95% <90% <80% <75% 20 days <95%<90% <85% <60% <50% 30 days <92% <85% <80% <50% <20%

Preferably, the daily dosage of tapentadol is within the range of from25 to 600 mg, preferably from 50 to 300 mg, more preferably from 50 to150 mg.

The reduction of the mean values for the depression scores due to theadministration of tapentadol over the time periods of 10, 20 and 30 daysare summarized as preferred embodiments E36 to E30 below. Each %-valueindicates the remaining mean depression score after the defined timeperiod relative to the initial mean depression score.

Time E36 E37 E38 E39 E40 10 days <99% <95% <90% <80% <75% 20 days <95%<90% <85% <60% <50% 30 days <92% <85% <80% <50% <20%

Preferably, the daily dosage of tapentadol is within the range of from25 to 600 mg, preferably from 50 to 300 mg, more preferably from 50 to150 mg.

Preferably, tapentadol is administered in form of a pharmaceuticalcomposition comprising tapentadol and at least one pharmaceuticallyacceptable additive and/or auxiliary substance.

Suitable pharmaceutically acceptable additives and/or auxiliarysubstances in the context of this invention include all the substancesknown to the expert from the prior art for realizing galenicalformulations. The choice of these auxiliary substances and the amountsthereof to be employed depend on whether the administration unit/dosageform is to be administered orally, intravenously, intraperitoneally,intradermally, intramuscularly, intranasally, buccally or locally.Formulations in the form of tablets, chewable tablets, coated tablets,capsules, granules, drops, juices or syrups are suitable for oraladministration, and solutions, suspensions, easily reconstitutable dryformulations and sprays are suitable for parenteral, topical andinhalatory administration. Suppositories for use in the rectum are afurther possibility. The use in a depot in dissolved form, a carrierfilm or a patch, optionally with the addition of agents which promotepenetration through the skin, are examples of suitable forms forpercutaneous administration.

Examples of pharmaceutically acceptable auxiliary substances andadditives for orally administrable units or dosage forms includedisintegrating agents, lubricants, binders, fillers, mold releaseagents, optionally solvents, flavorings, sugars, in particular carrieragents, diluents, dyestuffs, antioxidants etc. For suppositories, interalia, waxes and fatty acid esters can be used, and for compositions forparental administration carrier substances, preservatives, suspensionauxiliaries etc. can be used.

The dosage forms comprise preferably 0.05 wt.-% to 99.5 wt.-% oftapentadol, more preferably 0.1 to 90 wt.-%, still more preferably 0.5to 80 wt.-%, most preferably 1.0 to 50 wt.-% and in particular 5.0 to 20wt.-%.

Suitable pharmaceutically acceptable auxiliary substances include, forexample: water, ethanol, 2-propanol, glycerol, ethylene glycol,propylene glycol, polyethylene glycol, polypropylene glycol, glucose,fructose, lactose, sucrose, dextrose, molasses, starch, modified starch,gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose,methylcellulose, carboxymethyl cellulose, cellulose acetate, shellac,cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, naturallyoccurring and synthetic gums, gum acacia, alginates, dextran, saturatedand unsaturated fatty acids, stearic acid, magnesium stearate, zincstearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesameoil, coconut oil, groundnut oil, soya bean oil, lecithin, sodiumlactate, polyoxyethylene and polypropylene fatty acid esters, sorbitanfatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbicacid, tannic acid, sodium chloride, potassium chloride, magnesiumchloride, calcium chloride, magnesium oxide, zinc oxide, silicondioxide, titanium oxide, titanium dioxide, magnesium sulfate, zincsulfate, calcium sulfate, potash, calcium phosphate, dicalciumphosphate, potassium bromide, potassium iodide, talc, kaolin, pectin,crospovidone, agar and bentonite.

The administration units/dosage forms according to the invention may becontrolled release, delayed release, prolonged release/extended release,sustained release, repeat-action release, etc. Prolonged releaseadministration units/dosage forms are preferred.

The administration units/dosage forms according to the invention areprepared with the aid of means, devices, methods and processes which arewell-known in the prior art of pharmaceutical formulation, such as aredescribed, for example, in “Remington's Pharmaceutical Sciences”, ed. A.R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), inparticular in part 8, chapter 76 to 93.

Thus, e.g., for a solid formulation, such as a tablet, tapentadol can begranulated with a pharmaceutical carrier, e.g. conventional tabletconstituents, such as maize starch, lactose, sucrose, sorbitol, talc,magnesium stearate, dicalcium phosphate or physiologically acceptablegums, and pharmaceutical diluents, such as e.g. water, in order to forma solid composition which comprises tapentadol in homogeneousdistribution. Homogeneous distribution is understood here as meaningthat tapentadol is uniformly distributed over the entire composition, sothat this can easily be divided into unit dose forms, such as tablets,pills or capsules, having the same activity. The solid composition isthen divided into unit dose forms. The administration units according tothe invention can also be coated or compounded in another manner inorder to provide a dose form with delayed release. Suitable coatingcompositions are, inter alia, polymeric acids and mixtures of polymericacids with materials such as e.g. shellac, cetyl alcohol and/orcellulose acetate.

Tapentadol can be released in a delayed or prolonged or sustained mannerfrom administration units/dosage forms which can be used orally,rectally or percutaneously. Corresponding formulations, in particular inthe form of a “twice daily (bid)” preparation which has to be taken onlytwice a day (bid), are particularly preferred for the indicationaccording to the invention (cf. US-A-2005-58706).

Delayed or prolonged or sustained release of tapentadol may be achievedby administration units/dosage forms which contain tapentadol in amatrix, which contains e.g. 1 to 80% by weight, in particular 5 to 80 byweight, of one or more hydrophilic or hydrophobic polymers asphysiologically acceptable matrix forming agents and which comprisecellulose ethers and/or cellulose esters having a viscosity (determinedusing a Pharm. Eu. capillary viscosimeter) of 3,000 to 150,000 mPa s ina 2% by weight aqueous solution at 20° C. as physiologically acceptablematrix forming agents. Preferred physiologically acceptable matrixforming agents include polyethylene oxide having a molecular mass ofmore than 0.5 mio g/mol, cellulose ethers and/or cellulose esters havinga viscosity between 10,000, in particular 50,000 mPa s, and 150,000 mPas in a 2% by weight aqueous solution at 20° C. Particularly suitablephysiologically acceptable matrix forming agents may be selected fromthe group consisting of hydroxypropylmethyl celluloses (HPMC),hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methylcelluloses, ethyl celluloses and carboxymethyl celluloses and areselected, in particular, from the group consisting of HPMCs,hydroxyethyl celluloses and HPCs. HPMCs having a viscosity ofapproximately 100,000 mPa s, measured in a 2% by weight aqueous solutionat 20° C. are most preferred.

The administration units/dosage forms according to the invention canexist both as a simple tablet and as a coated tablet, for example as afilm tablet or dragee. The tablets are typically round and biconvex, butoblong tablet shapes which allow the tablet to be divided are alsopossible. Granules, spheroids, pellets or microcapsules which are pouredinto sachets or capsules or may be compressed to disintegrating tabletsare also possible within the scope of the invention.

Instead of a slow release matrix, it is also possible to use a normalrelease matrix with a coating which retards release of thepharmacologically active ingredient. For example, tapentadol can becontained in a conventional matrix of microcrystalline cellulose andoptionally further pharmaceutical auxiliaries such as binders, fillers,glidants, lubricants and flow regulators, which are covered or coatedwith a material controlling the slow release of tapentadol in an aqueousmedium. Suitable coating agents include, for example, water-insolublewaxes and polymers such as polymethacrylates (Eudragit or the like) orwater-insoluble celluloses, in particular ethyl cellulose. The coatingmaterial can optionally also contain water-soluble polymers such aspolyvinyl pyrrolidone, water-soluble celluloses such ashydroxypropylmethyl cellulose or hydroxypropyl cellulose, otherwater-soluble agents such as Polysorbate 80 or hydrophilic pore-formingagents such as polyethylene glycol, lactose or mannitol.

As an alternative or a supplement to the possibilities of a slow releasematrix in the delayed release or prolonged release or sustained releasedosage forms or of a normal release matrix with a coating which retardsthe release of tapentadol, an osmotically driven release system can alsobe used to achieve a slow release. Embodiments and examples of theactual production of osmotically driven release systems can be found inU.S. Pat. No. 4,765,989, U.S. Pat. No. 4,783,337, and U.S. Pat. No.4,612,008.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

EXAMPLE Aim and Design

The effectiveness of tapentadol hydrochloride PR and tapentadolhydrochloride IR in the treatment of pain in a subject suffering fromdepression and/or from anxiety, and in the treatment of depressionand/or of anxiety has been demonstrated in a clinical study in subjectswith severe and chronic nociceptive, mixed with neuropathic low backpain. A subgroup suffering from neuropathic pain due to lumbarradiculopathy was also investigated.

This was a multicenter, multinational, open-label, effectiveness phaseIIIb trial to evaluate effectiveness and safety of tapentadol prolongedrelease treatment in patients with inadequately managed, severe chroniclow back pain with or without a neuropathic pain component. Patientstaking WHO Step II analgesics discontinued those analgesics beforestarting study medication; patients taking Step I analgesics and/orcentrally acting co-analgesics continued on the same dose. Patients whoenrolled in the study and were taking WHO Step I or II analgesics had anaverage pain intensity score of >5 on an 11-point NRS-3 (average painover 3 days prior to assessment) at screening; patients who were takingno regular analgesic treatment had an average pain intensity score(NRS-3) of >6. All patients received tapentadol prolonged release(50-250 mg bid) for up to 12 weeks (5-week titration period and a 7-weekmaintenance period). Tapentadol immediate release (IR) 50 mg (≦twice aday, ≧4 hours apart) was permitted (combined total daily dose oftapentadol prolonged release and tapentadol IR, ≦500 mg/day). Theprimary efficacy endpoint was the change from Baseline to Week 6 (whentapentadol prolonged release doses were stable) in average painintensity on the 11-point NRS-3 using the last observation carriedforward (LOCF) for imputing missing scores. The painDETECT questionnairewas used to evaluate the likelihood of a neuropathic pain component oflow back pain; patients were classified as painDETECT “negative,”“unclear,” or “positive.” The population of patients classified aspainDETECT negative was limited to approximately 30% of the totalpopulation.

In the painDETECT positive trial population the “diagnosis of lumbarradiculopathy” was evaluated which was defined per study protocolaccording following criteria:

-   -   typical dermatomal pain (radiating beyond the knee towards the        foot, pain evoked by stretching within distribution of the        ischiadic/femoral nerve)    -   signs of root dysfunction:    -   such as sensory impairment, motor symptoms from compression of        lumbar nerve root (L4, L5, S1).    -   and/or absent or diminished quadriceps femoris or triceps surae        reflexes.    -   and/or quantitative sensory testing (QST) deficit and pain        distribution present in the same dermatomal area.

In subjects with neuropathic pain further characterization of thesymptoms was performed. These additional assessments referred explicitlyto the neuropathic component of the LBP (Neuropathic Pain SymptomInventory (NPSI), Short Form McGill Pain Questionnaire (SF-MPQ).NRS-3for pain radiating towards or into the leg).

All subjects completed Short Form-36 (SF-36) and EuroQoi-5 Dimension(EQ-5D) questionnaires and the Hospital Anxiety and Depression Scale(HADS). The Patient Global Impression of Change (PGIC) and Clinicalglobal impression of change (CGIC) were also used as secondaryendpoints. For both tests, patients completed the statement, “since Ibegan trial treatment, I would rate my overall condition as,” using 7possible responses (“very much worse” to “very much improved”). Adverseevents were recorded throughout the trial. Furthermore, 51.8% of thepainDETECT positive trial population had a “diagnosis of lumbarradiculopathy” as defined per study protocol.

Results

Short Form 36® Health Survey (SF-36®) scores: SF-36 physicalfunctioning, bodily pain, general health, role-emotional and physicalcomponent summary scores improved from Baseline to Week 12 for patientswho were painDETECT negative or unclear/positive (all P<0.05); for thosewho were unclear/positive, role-physical, vitality, social functioning,mental health, reported health transition and mental component summaryscores also improved (all P<0.05).

EuroQol-5 Dimension (EQ-5D) scores: the mean (SD) change from Baselineto Week 12 in the EQ-5D health status index score was 0.18 (0.25;P=0.0022) for patients who were painDETECT negative and 0.36 (0.32);P<0.0001) for those positive.

Hospital Anxiety and Depression Scale (HADS): Baseline mean (SD) HADSdepression (6.5[3.96] vs. 8.5[4.27]) and anxiety (6.2[4.10] vs.8.4[4.26]) scores were lower for patients with a painDETECT negative vs.an unclear/positive result, respectively. HADS depression and anxietyscores improved steadily from Baseline to Week 12 for patients who werepainDETECT unclear/positive (P<0.0001 at Visit 12 for depression andanxiety), but not significantly for those with a negative result. HADSdepression and anxiety scores improved steadily from Baseline to Week 12for patients with positive diagnosis of lumbar radiculopathy-neuropathicpain subset (0.0023 at Visit 12 for depression, p=0.0105 at Visit 12 foranxiety).

Patient Global Impression of Change: The percentage of patientsreporting a rating of “very much improved” or “much improved” on thePGIC increased from 15.1% (26/172) at Week 1 to 48.6% (67/138) at Week 6and 67.1% (61/91) at Week 12.

Clinical global impression of change (CGIC): The percentage of patientsreporting a rating of “very much improved” or “much improved” on theCGIC increased from 15.1% (26/172) at Week 1 to 50.7% (70/138) at Week 6and 68.2% (62/91) at Week 12.

Subject satisfaction with previous/new treatment: The percentage ofpatients reporting a rating of “excellent” or “very good” increased from0.0% (0/175) at Baseline to 29.7 (41/138) at Week 6 and 52.8% (48/91) atWeek 12.

In the following

-   (i) N is the number of subjects of the specified diagnosis group,-   (ii) n is the number of subjects with data available,-   (iii) “Mean” is the mean score of the subjects, i.e. the sum of all    scores is divided by the number of subjects,-   (iv) SD is the standard deviation,-   (v) “Median” is the median score of the subjects, i.e. the middle    score in the set of scores,-   (vi) “Range” is the range of scores of the subjects, i.e. the range    defined by the lowest and the highest score of the set of scores.    First, the depression scores are presented. The total number of    subjects in the clinical study: N=175

Depression score n Mean (SD) Median Range Screening 174 7.9 (4.37) 8.01-20 Baseline 173 7.9 (4.27) 8.0 0-21 Visit 1 164 7.8 (4.47) 7.0 0-20Visit 5 141 6.9 (4.26) 6.0 0-18 Visit 6 130 6.6 (4.41) 6.0 0-19 Visit 7127 6.1 (4.40) 6.0 0-18 Visit 8 119 6.2 (4.16) 6.0 0-17 Visit 9 87 6.1(4.48) 6.0 0-17 Visit 10 85 6.2 (4.66) 6.0 0-21 Visit 11 85 5.9 (4.59)5.0 0-17 Visit 12 89 5.7 (4.35) 5.0 0-18Total number of subjects with nociceptive pain: N=49

Depression score n Mean (SD) Median Range Screening 48 6.8 (4.17) 6.01-16 Baseline 49 6.5 (3.96) 6.0 0-15 Visit 1 43 6.1 (3.90) 5.0 0-15Visit 5 37 5.6 (3.68) 5.0 0-13 Visit 6 34 5.3 (4.03) 4.0 1-15 Visit 7 355.0 (3.63) 4.0 1-14 Visit 8 32 5.5 (3.90) 4.5 0-16 Visit 9 25 5.4 (3.49)5.0 1-12 Visit 10 24 5.5 (3.34) 5.5 1-12 Visit 11 23 5.6 (4.04) 5.0 0-14Visit 12 23 4.9 (3.13) 4.0 0-11Total number of subjects with presumed neuropathic pain component: N=41

Depression score n Mean (SD) Median Range Screening 41 7.4 (3.69) 7.01-17 Baseline 40 7.9 (3.84) 7.5 1-17 Visit 1 38 8.8 (4.59) 8.5 1-18Visit 5 33 7.5 (4.59) 7.0 0-18 Visit 6 30 7.5 (4.60) 7.5 0-17 Visit 7 327.0 (4.71) 6.5 0-18 Visit 8 28 6.4 (4.24) 6.0 1-14 Visit 9 19 6.4 (4.32)6.0 0-15 Visit 10 19 6.4 (5.34) 5.0 0-21 Visit 11 20 6.4 (5.11) 5.0 0-17Visit 12 21 6.2 (4.66) 5.0 0-17Total number of subjects with defined neuropathic pain: N=85

Depression score n Mean (SD) Median Range Screening 85 8.9 (4.63) 9.01-20 Baseline 84 8.7 (4.46) 8.5 0-21 Visit 1 83 8.3 (4.51) 8.0 1-20Visit 5 71 7.3 (4.29) 7.0 1-17 Visit 6 66 6.8 (4.41) 6.0 0-19 Visit 7 606.2 (4.56) 6.0 0-16 Visit 8 59 6.4 (4.28) 6.0 1-17 Visit 9 43 6.5 (5.06)6.0 0-17 Visit 10 42 6.5 (5.04) 6.0 0-19 Visit 11 42 5.9 (4.70) 5.5 0-15Visit 12 45 5.8 (4.76) 5.0 0-18Total number of subjects with presumed or defined neuropathic paincomponent: N=126

Depression score n Mean (SD) Median Range Screening 126 8.4 (4.38) 8.01-20 Baseline 124 8.5 (4.27) 8.0 0-21 Visit 1 121 8.5 (4.52) 8.0 1-20Visit 5 104 7.4 (4.37) 7.0 0-18 Visit 6 96 7.1 (4.46) 7.0 0-19 Visit 792 6.5 (4.61) 6.0 0-18 Visit 8 87 6.4 (4.24) 6.0 1-17 Visit 9 62 6.5(4.81) 6.0 0-17 Visit 10 61 6.5 (5.09) 6.0 0-21 Visit 11 62 6.0 (4.80)5.0 0-17 Visit 12 66 5.9 (4.70) 5.0 0-18Total number of subjects with positive diagnosis of lumbarradiculopathy-neuropathic pain subset: N=44

Depression score n Mean (SD) Median Range Screening 44 8.5 (4.70) 8.52-20 Baseline 44 8.2 (4.09) 8.0 0-17 Visit 1 44 7.5 (3.69) 7.5 1-15Visit 5 40 6.7 (3.77) 6.0 1-14 Visit 6 38 6.3 (3.67) 6.0 1-13 Visit 7 345.4 (3.85) 5.0 0-14 Visit 8 35 5.8 (3.71) 6.0 1-14 Visit 9 24 6.2 (4.63)7.5 1-14 Visit 10 25 6.2 (4.50) 7.0 0-13 Visit 11 26 6.0 (4.69) 6.5 0-14Visit 12 27 5.3 (4.09) 5.0 0-12Second, the anxiety scores are presented. The total number of subjects:N=175

Anxiety score n Mean (SD) Median Range Screening 174 8.1 (3.99) 8.0 1-19Baseline 173 7.8 (4.32) 7.0 0-18 Visit 1 164 7.6 (4.28) 7.0 0-18 Visit 5141 6.8 (3.94) 7.0 0-17 Visit 6 130 6.6 (4.02) 6.0 0-18 Visit 7 127 5.9(3.99) 6.0 0-18 Visit 8 119 5.6 (3.95) 5.0 0-18 Visit 9 87 5.7 (4.10)4.0 0-19 Visit 10 85 5.6 (4.16) 5.0 0-19 Visit 11 85 5.4 (3.91) 5.0 0-14Visit 12 89 5.2 (3.73) 4.0 0-13Total number of subjects with nociceptive pain: N=49

Anxiety score n Mean (SD) Median Range Screening 48 6.7 (3.80) 6.5 1-15Baseline 49 6.2 (4.10) 5.0 0-16 Visit 1 43 5.9 (4.19) 6.0 0-18 Visit 537 6.1 (3.80) 5.0 0-14 Visit 6 34 5.8 (4.68) 5.0 0-18 Visit 7 35 5.6(4.15) 5.0 0-18 Visit 8 32 5.4 (4.40) 4.0 0-18 Visit 9 25 4.6 (3.34) 4.00-13 Visit 10 24 4.7 (3.21) 4.0 0-11 Visit 11 23 4.8 (3.77) 4.0 0-14Visit 12 23 4.5 (3.65) 3.0 0-13Total number of subjects with presumed neuropathic pain component: N=41

Anxiety score n Mean (SD) Median Range Screening 41 8.3 (3.68) 8.0 1-17Baseline 40 8.3 (4.15) 7.0 2-17 Visit 1 38 7.9 (4.52) 7.0 2-17 Visit 533 6.7 (4.22) 7.0 0-15 Visit 6 30 6.9 (3.99) 6.0 1-16 Visit 7 32 5.9(4.08) 5.5 0-13 Visit 8 28 4.9 (4.04) 4.0 0-14 Visit 9 19 6.1 (5.10) 6.00-19 Visit 10 19 5.5 (5.46) 4.0 0-19 Visit 11 20 5.1 (4.25) 4.0 0-13Visit 12 21 4.8 (3.67) 4.0 0-12Total number of subjects with defined neuropathic pain: N=85

Anxiety score n Mean (SD) Median Range Screening 85 8.9 (4.07) 9.0 1-19Baseline 84 8.5 (4.33) 8.5 0-18 Visit 1 83 8.3 (4.01) 8.0 0-18 Visit 571 7.2 (3.89) 8.0 0-17 Visit 6 66 6.9 (3.66) 6.0 0-16 Visit 7 60 6.1(3.91) 6.0 0-16 Visit 8 59 6.0 (3.66) 5.0 0-14 Visit 9 43 6.1 (3.99) 5.01-16 Visit 10 42 6.1 (3.98) 6.0 0-16 Visit 11 42 5.9 (3.84) 5.5 0-13Visit 12 45 5.7 (3.80) 5.0 0-13Total number of subjects with presumed or defined neuropathic paincomponent: N=126

Anxiety score n Mean (SD) Median Range Screening 126 8.7 (3.94) 9.0 1-19Baseline 124 8.4 (4.26) 8.0 0-18 Visit 1 121 8.2 (4.16) 8.0 0-18 Visit 5104 7.0 (3.98) 7.0 0-17 Visit 6 96 6.9 (3.75) 6.0 0-16 Visit 7 92 6.0(3.95) 6.0 0-16 Visit 8 87 5.7 (3.80) 5.0 0-14 Visit 9 62 6.1 (4.32) 5.00-19 Visit 10 61 5.9 (4.46) 5.0 0-19 Visit 11 62 5.6 (3.96) 5.0 0-13Visit 12 66 5.4 (3.76) 5.0 0-13Total number of subjects with positive diagnosis of lumbarradiculopathy-neuropathic pain subset: N=44

Anxiety score N Mean (SD) Median Range Screening 44 8.9 (4.06) 9.0 1-17Baseline 44 8.6 (4.23) 9.0 0-18 Visit 1 44 8.7 (3.64) 9.0 1-18 Visit 540 6.8 (3.39) 7.5 1-15 Visit 6 38 7.1 (3.46) 7.5 1-13 Visit 7 34 6.1(3.85) 6.0 0-15 Visit 8 35 5.9 (3.74) 5.0 0-13 Visit 9 24 6.2 (4.01) 5.01-13 Visit 10 25 6.1 (3.85) 6.0 0-13 Visit 11 26 6.3 (4.25) 6.5 0-13Visit 12 27 5.7 (3.59) 6.0 0-11

The foregoing clinical data clearly demonstrate that tapentadol exhibitsa significant efficacy against depression and anxiety.

The changes from baseline at visits 6, 8 and 12 are summarized in thefollowing tables:

Depression:

presumed or presumed defined lumbar defined nociceptive neuropathicneuropathic radiculopathy neuropathic total Visit 6 n 34 29 65 38 94 128Mean (SD) −1.0 (3.15) −0.4 (3.55) −1.7 (3.43) −1.7 (3.23) −1.3 (3.50)−1.2 (3.40) Median −1.0 −0.0 −2.0 −1.0 −1.0 −1.0 Min, Max −11, 5  −12, 4−10, 8 −9, 4 −12, 8 −12, 8 95% CI [−2.1; 0.1] [−1.8; 0.9] [−2.6; −0.9][−2.7; −0.6] [−2.0; −0.6] [−1.8; −0.6] p-value# 0.0813 0.5354 0.00020.0027 <0.0005 <0.0001 Visit 8 n 32 27 58 35 85 117 Mean (SD) −0.8(2.31) −1.0 (3.13) −2.3 (3.33) −2.1 (3.54) −1.9 (3.30) −1.6 (3.09)Median −1.0 −1.0 −1.5 −1.0 −1.0 −1.0 Min, Max −8, 4 −12, 3 −12, 3 −10,3  −12, 3 −12, 4 95% CI [−1.6; 0.0] [−2.2; 0.2] [−3.2; −1.4] [−3.3;−0.9] [−2.6; −1.2] [−2.1; −1.0] p-value# 0.0551 <0.1084 <0.0001 0.0014<0.0001 <0.0001 Visit 12 n 23 21 45 27 66 89 Mean (SD) −0.5 (2.86) −1.5(3.30) −2.2 (3.31) −2.1 (3.30) −2.0 (3.30) −1.6 (3.24) Median 0.0 −2.0−2.0 −1.0 −2.0 −2.0 Min, Max −5, 4 −10, 6  −9, 6 −9, 3 −10, 6 −10, 6 95%CI [−1.7; 0.8] [−3.0; 0.0] [−3.2; −1.2] [−3.5; −0.8] [−2.8; −1.2] [−2.3;−0.9] p-value# 0.4309 0.0534 0.0001 0.0023 <0.0001 <0.0001

Anxiety:

presumed or presumed defined lumbar defined nociceptive neuropathicneuropathic radiculopathy neuropathic total Visit 6 n 34 29 65 38 94 128Mean (SD) −0.3 (2.93) −1.6 (3.58) −1.4 (3.44) −1.4 (3.88) −1.5 (3.47)−1.2 (3.36) Median 0.0 −1.0 −1.0 −0.5 −1.0 −1.0 Min, Max −7, 5  −9, 9−10, 5 −10, 5 −10, 9 −10, 9 95% CI [−1.3; 0.7] [−2.9; −0.2] [−2.3; −0.6][−2.6; −0.1] [−2.2; −0.7] [−1.7; −0.6] p-value# 0.5242 0.0271 0.00150.0361 <0.0001 0.0002 Visit 8 n 32 27 58 35 85 117 Mean (SD) −0.7 (3.88)−2.9 (3.11) −2.2 (3.77) −2.4 (4.23) −2.4 (3.57) −1.9 (3.72) Median −1.0−2.0 −2.0 −1.0 −2.0 −2.0 Min, Max  −7, 14 −11, 2 −13, 5 −13, 5 −13, 5 −13, 14 95% CI [−2.1; 0.7] [−4.1; −1.7] [−3.2; −1.2] [−3.9; −1.0][−3.2; −1.6] [−2.6; −1.3] p-value# 0.3027 <0.0001 <0.0001 0.0018 <0.0001<0.0001 Visit 12 n 23 21 45 27 66 89 Mean (SD) −0.8 (2.82) −3.1 (3.16)−2.3 (4.14) −2.2 (4.11) −2.5 (3.85) −2.1 (3.67) Median −1.0 −3.0 −2.0−2.0 −2.0 −2.0 Min, Max −9, 4 −13, 0 −11, 6 −10, 4 −13, 6 −13, 6 95% CI[−2.0; 0.4] [−4.5; −1.7] [−3.5; −1.0] [−3.8; −0.6] [−3.5; −1.6] [−2.9;−1.3] p-value# 0.1744 0.0002 0.0006 0.0105 <0.0001 <0.0001

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A method of treating pain in a subject, said method comprisingadministering to the subject a therapeutically effective amount oftapentadol as the only pharmacologically active ingredient, wherein thesubject suffers from depression and/or anxiety.
 2. (canceled) 3.(canceled)
 4. The method according to claim 1, wherein the tapentadol isadministered orally.
 5. The method according to claim 1, wherein thetapentadol is administered once daily or twice daily.
 6. The methodaccording to claim 1, wherein the tapentadol is administered at a dailydose within the range of from 25 to 600 mg.
 7. The method of treatingpain according to claim 1, wherein the pain is moderate or severe. 8.The method of treating pain according to claim 1, wherein the pain ischronic pain.
 9. The method according to claim 8, wherein the chronicpain is pain selected from the group consisting of cancer pain,chemotherapy-induced pain, upper back pain, low back pain, inflammatorypain including pain associated with rheumatic diseases, arthritic pain,ankylosing spondylitis, myofascial pain, pain associated withmusculo-skeletal disorders, muscle pain, skeletal pain, joint pain,chronic pain associated with fibromyalgia, pain from strains or sprains,persistent post-operative pain, persistent posttraumatic pain, renalcolic, irritable bowel syndrome-related pain, gastrointestinal pain,pelvic pain, abdominal pain, ischemic pain, angina pain, pain associatedwith claudication, pain accompanying myocardial infarction, vascularpain, central nervous system trauma, facial pain, migraine-related pain,headache-related pain, orofacial pain, persistent pain deriving fromdamaged or inflamed somatic tissue, and combinations of two or more ofthe foregoing.
 10. The method of treating pain according to claim 1,wherein the pain is selected from the group consisting of neuropathicpain, nociceptive pain, psychogenic pain, phantom pain and combinationsof two or more of the foregoing.
 11. The method of treating painaccording to claim 1, wherein the pain is neuropathic pain.
 12. Themethod according to claim 11, wherein the neuropathic pain is selectedfrom the group consisting of diabetic neuralgia, monoradiculopathies,trigeminal neuralgia, post-herpetic neuralgia, persistent postoperativeor posttraumatic pain, hyperalgia, allodynia, fibromyalgia, complexregional pain syndrome, pain associated with multiple sclerosis,AIDS-related neuropathy, thalamic pain, paraplegic pain caused bymyelopathy, anesthesia dolorosa, low back pain, reflex sympatheticdystrophy/causalgia, cancer pain, chemotherapy-induced pain,post-thoracotomy pain, entrapment neuropathy, and peripheral neuropathy.13-15. (canceled)
 16. The method according to claim 1, wherein thetapentadol is used for a) the treatment of pain in the subject sufferingfrom depression or from anxiety; e) the treatment of pain and thesimultaneous treatment of depression or anxiety; or f) the treatment ofpain and simultaneous inhibition of depression or anxiety.